Exploring Drug Repurposing For Arboviral Infections Through Cavitomix

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMAug 2 2024

Due to climate change, arthropod vectors' rapidly changing geographic distributions increase the risk of arboviruses or arthropod-borne viruses such as Zika, Dengue, and Chikungunya viruses that spread through mosquitoes.

There are no approved antivirals for some of these arboviral diseases yet, and developing novel inhibitors has a high failure rate.

In a recent study published in Viruses, Austrian researchers used the CavitOmiX drug discovery method, developed by the drug and enzyme discovery platform Innophore, to scan binding sites of existing, approved drugs that can be used off-label to treat arboviral infections.

Study: CavitOmiX Drug Discovery: Engineering Antivirals with Enhanced Spectrum and Reduced Side Effects for Arboviral Diseases. Image Credit: rfranca/Shutterstock.com

Background

Climate change is resulting in rapid changes in the landscape and, subsequently, arthropod distributions. These changes increase the risk of arthropod vector-borne and often zoonotic diseases, potentially resulting in more pandemics.

The distribution of mosquitoes of the species Aedes albopictus and Aedes aegypti have undergone significant alterations due to climate change, and these insects bring with them arthropod-borne viruses such as Zika virus, Dengue virus, and Alphavirus chikungunya.

Although nanoparticle-based and live attenuated vaccines have been developed for some arboviral diseases, no effective antiviral treatments exist to treat these infections or protect immunocompromised individuals.

Furthermore, developing novel drugs and inhibitors is time-consuming and carries a high risk of failure in the clinical trial phases.

About the Study

In the current study, the researchers examined drug repurposing, where drugs already approved for treating other diseases are examined for off-label use. It provides an alternative to novel drug discovery while reducing the time and resources spent on clinical trials.

The researchers aimed to discover potential small-molecule inhibitors that target the non-structural protein 3 (nsP3) of Alphavirus chikungunya or CHIKV that causes chikungunya.

The virus belongs to the Togaviridae family, and symptoms of CHIKV infection include headaches, fever, rash, and severe joint pain, which persists and results in long-term arthritis or arthralgia in about 30% of the cases.

The non-structural protein 3 of the virus is a promising target for drugs targeting CHIKV since it is essential for the replication and transcription of the viral genome.

Inhibitors that can bind to adenosine diphosphate (ADP)-ribose binding site of the nsP3 are known to prevent CHIKV viral replication. Still, there are concerns about the inhibitors also binding to the macrodomains in humans involved in the ADP's ribosylation.

Therefore, to refine candidate inhibitors that could potentially induce side effects, the researchers used the discovery method called CavitOmiX, developed by the Austrian drug discovery platform Innophore.

Along with NVIDIA, Innophore has also recently developed a comprehensive human protein structure dataset that has open-access information on thousands of binding sites, which can be used to identify off-target sites.

CavitOmiX was used to screen three-dimensional (3D) point-cloud databases of binding sites of existing approved drugs with known toxicity profiles.

The researchers used a genetic algorithm that refined the candidate inhibitors through an iterative process and used the NVIDIA and Innophore proteome database to ensure that the inhibitors exhibited low off-target binding.

The algorithm was also used to identify lead inhibitor candidates that showed strong binding to viral variants recognized through continuous mutation monitoring.

Major Findings

The study showed that through the use of CavitOmiX and the human proteomic database developed by Innophore and NVIDIA, existing drugs could be investigated for drug repurposing.

They used the protocol to identify potential drugs that can be applied off-label to treat chikungunya by targeting the ADP-ribose binding site of the nsP3 protein in CHIKV. This method also helped identify potential off-target side effects of the candidate inhibitors in the early stages of the drug discovery process.

The researchers discovered that the antiviral Remdesivir, and GS-441542, its analog, were promising inhibitor candidates to treat chikungunya.

Naproxen, which is labeled for use as a pain medication, was also a potential drug candidate against CHIKV. The cancer drug Sunitinib was also identified as a possible inhibitor of CHIKV, but it presented a high chance of side effects.

Furthermore, the study found that the proteins from which these small molecule inhibitors originated showed no similarity in sequence or structure with nsP3 in CHIKV, highlighting the ability of CavitOmiX to identify potential drugs that might otherwise be overlooked by approaches focusing on structure and sequence similarity.

Conclusions

Overall, the study highlighted the value of the drug discovery method CavitOmiX in screening existing proteomic databases to identify approved drugs that could potentially be used off-label to treat arboviral infections such as chikungunya, dengue, and zika virus infections that currently do not have approved antivirals.

CavitOmiX can significantly improve drug repurposing by identifying broad-spectrum drugs with known safety profiles and low off-target effects that can be used to treat viral diseases for which therapies have not yet been developed.